The present invention relates to wound therapy, and in particular to the therapeutic treatment of hypertrophic scar tissue.
Scar tissue is formed during healing of wounds, caused for example by burn, traumatic injury and elective operative incisions. Often unpredictably, hypertrophy of the scar tissue occurs. Hypertrophic scar formation is characterized by the accumulation of collagen type III out of proportion to collagen type I.
Current procedures and materials for wound treatment include the use of compounds with potentially serious side effect, to highly invasive excisional procedures.
In accordance with one aspect of the invention, a composition for the therapeutic treatment of hypertrophic scar tissue is provided, comprising a non-toxic transglutaminase inhibitor having a free amino group, or a pharmaceutically acid addition salt thereof, and a pharmaceutically acceptable carrier or diluent.
According to another aspect of the invention, a method of treating hypertrophic scar tissue is also provided comprising applying to the scar tissue an effective amount of a non-toxic transglutaminase inhibitor having a free amino group, or a pharmaceutically acid addition salt acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier or diluent.
Tranglutaminases are enzymes present in plasma and various tissues which form isopeptide bonds between reactive glutaminyl groups an the e-amino group of lysine in certain proteins. For example, type III procollogen has been shown to be a specific and avid substrate for transglutominase. During skin wound healing it appears that type III procollagen amino peptide (PIIP) is cross-linked to other components of the wound matrix, such as fibrin and fibronectin, by tissue tranglutominase. It is therefore hypothesized that if a transglutaminase inhibitor having a free amino group is introduced to the wound site, its free amino group will preferentially bind to the glutominyl group, and thus inhibit the intended protein substrated from cross-linking, forming an inert analog-amine adduct instead.
Known non-toxic transglutaminase inhibitors of this type include aminoacetonitrile,(dansyl) cadaverine (1,5-diaminopentane), spermidine and putrescine (1,4-diaminobutane). All of these compounds are non-toxic primary amines.
More specifically, aminoacetonitrile is a primary aliphatic lower-alkyl (C1-5) monoamine. Spermidine is a primary aliphatic aklylamine. Putrescine and (dansyl) cadaverine are primary aliphatic lower-alkyl (C1-5) polyamines. Other similar, non-toxic primary amines of these types are also contemplated.
It will be appreciated by those skilled in the art that the active compounds may be usefully applied in the form of pharmaceutically acceptable acid addition salts such as hydrochlorides and hydrogen sulfates.
The pharmaceutically acceptable carrier is typically a eutectic cream or ointment to facilitate spreading over the wound area. For topical application, mineral oil has been found particularly suitable. Other suitable carriers include polyethylene glycols.
For topical applications, the effective amount of the active compound is in the range of 25 to 100 mM. and preferably about 50 mM.
Once the composition is applied to the wound it may advantageously be occiuded with a dressing or incorporated into a transepidermal patch dressing.
It will be appreciated that, although the compositions according to the invention are particularly useful for topical application to external wounds, it is also to be expected to be of value in the treatment of internal scar tissue. In such cases, the composition may be applied by catheter infusion or by an implantable time release mechanism. One specific example is diffusion through the elastomer coating of a breast implant.